Open Access<p>A Novel Splice-Site Mutation in the <em>ELN</em> Gene Suggests an Alternative Mechanism for Vascular Elastinopathies</p>
Author(s) -
Camilo Andres Velandia-Piedrahita,
Adrien Morel,
Dora Janeth Fonseca-Mendoza,
Manuel Huertas-Quiñones,
David Castillo,
Juan Diego Bonilla,
Camilo José Hernandez-Toro,
Marta-Catalina Miranda-Fernández,
Carlos Martín Restrepo,
Rodrigo Cabrera
Publication year - 2020
Publication title -
application of clinical genetics
Language(s) - English
Resource type - Journals
ISSN - 1178-704X
DOI - 10.2147/tacg.s282240
Subject(s) - exon , haploinsufficiency , elastin , tropoelastin , rna splicing , gene , genetics , mutation , intron , alternative splicing , splice site mutation , biology , rna , phenotype
The ELN gene encodes elastin, a fundamental protein of the extracellular matrix that confers elasticity to different tissues including blood vessels. The formation of elastin fibers is a complex process involving monomer coacervation and subsequent crosslinking. Mutations in exons 1-29 of the ELN gene have been linked to supravalvular aortic stenosis (SVAS) whereas mutations in exons 30-33 are associated with autosomal dominant cutis laxa (ADCL). This striking segregation has led to the hypothesis that distinct molecular mechanisms underlie both diseases. SVAS is believed to arise through haploinsufficiency while ADCL is hypothesized to be caused by a dominant negative effect. Here, we describe a patient with SVAS harboring a novel splice-site mutation in the last exon of ELN . The location of this mutation is not consistent with current knowledge of SVAS, since all mutations reported in the C-terminus have been found in ADCL patients, and a thorough evaluation did not reveal significant skin involvement in this case. RT-PCR analysis of skin tissue showed that C-terminal mutations in the region can lead to the production of aberrant transcripts through intron retention and activation of cryptic splice sites and suggest that disruption of the very last exon can lead to functional haploinsufficiency potentially related to SVAS.